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Human-specific CHRFAM7A protects against radiotherapy-induced lacrimal gland injury by inhibiting the p38/JNK signalling pathway and oxidative stress.

ABSTRACT: Radiotherapy-induced lacrimal gland injury often causes dry eye. Oxidative stress and local inflammation are the primary consequences of radiotherapy-induced injury. The most recent research shows that the human-specific gene CHRFAM7A plays an important role in inflammation. However, the effect of CHRFAM7A on radiotherapy-induced lacrimal gland injury remains unclear. In this study, humanized mice were successfully generated via the transplantation of human peripheral blood mononuclear cells that expressed human-specific genes. After radiation, the CHRFAM7A gene was highly expressed in the lacrimal glands of humanized mice, in which it protected the function of the lacrimal gland after radiotherapy. CHRFAM7A down-regulated radiotherapy-induced inflammation by suppressing p38/JNK signalling. CHRFAM7A also inhibited oxidative stress in the haematopoietic system after radiotherapy. Further signalling pathway analyses indicated that CHRFAM7A suppressed Akt (protein kinase B, PKB) phosphorylation. CHRFAM7A may therefore be a therapeutic target in radiation-induced lacrimal gland injury.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC6965404 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Human-specific CHRFAM7A protects against radiotherapy-induced lacrimal gland injury by inhibiting the p38/JNK signalling pathway and oxidative stress.

Zhang Yanqing Y Qian Jiang J Ren Hui H Meng Fengxi F Ma Ruiqi R Xu Binbin B

International journal of clinical and experimental pathology 20170801 8

Radiotherapy-induced lacrimal gland injury often causes dry eye. Oxidative stress and local inflammation are the primary consequences of radiotherapy-induced injury. The most recent research shows that the human-specific gene CHRFAM7A plays an important role in inflammation. However, the effect of CHRFAM7A on radiotherapy-induced lacrimal gland injury remains unclear. In this study, humanized mice were successfully generated via the transplantation of human peripheral blood mononuclear cells tha ...[more]

PMID: 31966770

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Project description:BackgroundAqueous-deficient dry eye disease (ADDED) resulting from dysfunction of the lacrimal gland (LG) is currently incurable. Although LG stem/progenitor cell-based therapy is considered to be a promising strategy for ADDED patients, the lack of a reliable serum-free culture method to obtain enough lacrimal gland stem cells (LGSCs) and the basic standard of LGSC transplantation are obstacles for further research.MethodsAdult mouse LGSCs were cultured in Matrigel-based 3D culture under serum-free culture condition, which contained EGF, FGF10, Wnt3A, and Y-27632. LGSCs were continuously passaged over 40 times every 7 days, and the morphology and cell numbers were recorded. LGSCs were induced to differentiate to ductal cells by reducing Matrigel rigidity, while fetal bovine serum was used for the induction of acinar cells. RT-PCR or qRT-PCR analysis, RNA-sequence analysis, H&E staining, and immunofluorescence were used for characterization and examining the differentiation of LGSCs. LGSCs were allotransplanted into diseased LGs to examine the ability of repairing the damage. The condition of eye orbits was recorded using a camera, the tear production was measured using phenol red-impregnated cotton threads, and the engraftments of LGSCs were examined by immunohistochemistry.ResultsWe established an efficient 3D serum-free culture for adult mouse LGSCs, in which LGSCs could be continuously passaged for long-term expansion. LGSCs cultured from both the healthy and ADDED mouse LGs expressed stem/progenitor cell markers Krt14, Krt5, P63, and nestin, had the potential to differentiate into acinar or ductal-like cells in vitro and could engraft into diseased LGs and relieve symptoms of ADDED after orthotopic injection of LGSCs.ConclusionWe successfully established an efficient serum-free culture for adult mouse LGSCs aiming at LG repair for the first time. Our approach provides an excellent theoretical and technical reference for future clinical research for ADDED stem cell therapy.

Dataset Information

Human-specific CHRFAM7A protects against radiotherapy-induced lacrimal gland injury by inhibiting the p38/JNK signalling pathway and oxidative stress.

Publications

Human-specific CHRFAM7A protects against radiotherapy-induced lacrimal gland injury by inhibiting the p38/JNK signalling pathway and oxidative stress.

Similar Datasets

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